Engineered biosynthesis of bacterial polyketides in Saccharomyces cerevisiae

Modular type I PKS carry multiple modules and catalyze the condensation reactions in an assembly line manner. Polyketide synthases are amendable to engineering efforts, since each PKS module has its own substrate-selecting domain (AT), which we can exchange with other AT domains to introduce functional groups into the carbon backbone. On the other hand, the multi-domain structure makes these proteins very large and often hard to express in a non-native context. Only three modular PKS pathways have been reconstituted in E. coli over the last twenty years while the number of new PKS sequences is constantly increasing. The model yeast S. cerevisiae could be a better expression and production host compared to E.coli, since yeast naturally express larger proteins containing multiple domains. We are establishing S. cerevisiae as a PKS expression platform by using an in vivo, in vitro as well as in silico approach to understand the host-specificity of PKS proteins. Furthermore we have implemented two different polyketide precursor supply pathways to increase the diversity of polyketides produced by yeast.